tbuckley/cabot-search huggingface dataset:
The efficacy and safety of sequential use of anlotinib and <sup>131</sup>I for locally advanced or metastatic differentiated thyroid cancer: A single-arm phase II clinical trial.
Authors: Hongjun Song, Xian Qiu, Ziyan He, Libo Chen
Journal: Journal of Clinical Oncology (2023)

e18102 Background: Locally advanced or metastatic differentiated thyroid cancer (DTC) commonly responds poorly to radioiodine ( 131 I) treatment alone. Tyrosine kinase inhibitors, however, have exerted promising antitumor activity in multiple advanced solid tumors. This study aimed to investigate the efficacy and safety of sequential use of anlotinib and 131 I for the treatment of locally advanced or metastatic DTC. Methods: This is a single-arm phase II open-label clinical trail. The key eligibility criteria included locally advanced or metastatic 131 I-avid DTC, ECOG PS of 0-1, and at least one measurable lesion. Previous tyrosine kinase inhibitor was not allowed. Patients initially received anlotinib (12 mg QD, 2 weeks on/1 week off ) for 4 cycles. At the beginning of 13 th week when levothyroxine had been discontinued for 4 weeks, diagnostic 131 I whole body scan (Dx-WBS) was performed, and those with 131 I-avid lesions were immediately identified to undergo 131 I treatment. The primary endpoint was objective response rate (ORR) . The secondary endpoints included disease control rate (DCR), biochemical response rate (BRR), time-to-response (TTR), progression-free survival (PFS), and safety. Results: From June 2021 to December 2022, a total of 16 patients with locally advanced or metastatic DTC were included. At the data cut off, 8 patients (4 males and 4 females) were withdrawn from the trial due to negative Dx-WBS, and the remaining 8 patients were subsequently treated with 131 I. Six patients who had completed at least one cycle of sequential treatment were eligible for data analysis. Partial response and stable disease were found in 2 (33.33%) and 3 (50%) patients, respectively. An ORR of 33.33% [95% CI, 4.33-77.72], a DCR of 83.33% [95% CI, 35.88-99.58], a BRR of 100% [95% CI, 54.07-100.00], and a TTR of 6.34 months [95% CI, 5.85-NE] were achieved. Median PFS was not reached. Grade 3 adverse events occurred in 2 (33.33%) of the 6 subjects, including pain owing to skeletal metastasis in one patient and drug-related hypertention in the other. Conclusions: This study firstly demonstrates the favorable efficacy and safety of sequential therapy with tyrosine kinase inhibitor and 131 I, suggesting anlotinib as a adjuvant option for 131 I treatment of locally advanced or metastatic DTC. Randomized controlled studies on sequential therapy versus 131 I treatment are warranted. Clinical trial information: ChiCTR2100045178 .
Rates of emergency department visits and acute-care hospital admissions after starting chemotherapy or having surgery across six community-based cancer centers.
Authors: Michael J. Hassett, Christine Cronin, Angela Tramontano, Sandra L. Wong, Hajime Uno, Roshan Paudel, Jessica J Bian, Don S. Dizon, Hannah W. Hazard-Jenkins, Raymond U. Osarogiagbon, Deborah Schrag
Journal: Journal of Clinical Oncology (2023)

6621 Background: Cancer patients who start chemotherapy or have surgery are at risk for serious adverse events, which can include emergency department visits (EDV) and acute-care hospital admissions (ADM). These events are relevant to patients, clinicians, health systems, and policy makers. Few studies have described the frequency and predictors of EDVs and ADMs in the routine care setting. We sought to address this knowledge gap, and to describe the impact of the COVID pandemic on these events, using data from the SIMPRO consortium of six US-based health systems. Methods: In 2019, SIMPRO started a phased deployment of an electronic health record-integrated symptom management program (eSyM) as part of the routine care provided to patients with a suspected or confirmed gastrointestinal, thoracic, and gynecologic malignancy. eSyM prompts patients to complete symptom questionnaires and provides symptom management resources for 180 days after starting chemotherapy and 60 days following surgery. This analysis includes all patients, whether they used eSyM resources or not. Outcomes, which were measured using EHR-based encounter data, included the rates of EDVs and ADMs at 30 and 90-days after starting chemotherapy or following discharge from surgery. To account for potential confounding, we used multivariable logistic regression for the 30-day outcomes and Cox regression for the 90-day outcomes. Results: From September 2019-December 2022, 8664 patients started chemotherapy and 11,578 had surgery, with 3075 and 2587 patients, respectively, experiencing at least one outcome event (Table). 90-day outcomes varied significantly across health systems for chemotherapy (EDV 2-21%, ADM 5-28%) and surgery (EDV 7-14%, ADM 9-18%) patients. In multivariable analyses, patients who reported an employment status of disabled were more likely to report an EDV (OR 1.73-1.96) and an ADM (ORs 1.52-1.96). Widowed status was associated with greater odds of having an ADM (ORs 1.29-1.30), but not an EDV. Cox regression found chemotherapy recipients experienced lower hazards of an EDV, but not an ADM, during 2020 (coinciding with the start of the COVID pandemic). For surgery patients, there was no significant association between calendar year and EDVs or ADMs. [p&lt;0.001 for all reported values]. Conclusions: A meaningful proportion of patients who started chemotherapy or had surgery for a suspected or confirmed malignancy in the routine-care setting had an EDV or ADM within 90 days. Most events occurred within 30 days. Further work is required to ascertain how many of these encounters are avoidable and what structural or procedural interventions could improve outcomes. Clinical trial information: NCT03850912 . [Table: see text]
Response to subsequent platinum-based chemotherapy post PARP inhibitor in recurrent epithelial ovarian cancer.
Authors: Genevieve MacAulay Vacheresse, Elham Sabri, Sheryl Domingo, Tien Le
Journal: Journal of Clinical Oncology (2023)

5578 Background: Maintenance therapy with PARP inhibitors (PARPi) can increase progression free survival (PFS) for recurrent or metastatic platinum-sensitive epithelial ovarian cancer (EOC). Little is known about disease trajectory following treatment with these agents, though some evidence suggests a decreased response to subsequent platinum-based chemotherapy. This retrospective cohort study assessed real-world response rates to platinum-based chemotherapy for recurrent high grade EOC following treatment with a PARPi. Methods: All patients prescribed a PARPi as maintenance therapy for recurrent or metastatic EOC at the Ottawa Regional Cancer Center (ORCC) from September 2017 to May 2022 were included. PFS following penultimate therapy (line of therapy preceding PARPi initiation) as well as the PFS following subsequent platinum-based chemotherapy in patients with disease progression more than 6 months after penultimate therapy were calculated. Incidence of platinum resistance in patients with disease progression following PARPi therapy was determined. Results: 91 patients were included in the analysis including 54 patients on niraparib and 36 patients on olaparib. Follow-up after initiation of PARPi ranged from 4.6 months to 62.0 months with a median of 16.3 months. 54 (59.3%) of patients experienced disease progression after initiation of PARPi therapy, including 10 (11.0%) who progressed within 6 months of their penultimate therapy. Of the 44 patients who experienced disease progression more than 6 months following penultimate therapy, 32 (72.7%) were rechallenged with platinum-based chemotherapy. Of these, 16 (50.0%) experienced further disease progression with 14 (43.8%) progressing within 6 months of their platinum rechallenge. Median PFS following platinum rechallenge was 4.4 months (from 0.8 months to 34.9 months), significantly lower than previous reports. Conclusions: Patients who experienced disease progression following PARPi therapy showed a poor response to subsequent platinum-based chemotherapy, even when progression occurred more than 6 months after completion of their penultimate platinum-based chemotherapy. This supports the theory that PARPi resistance may be a surrogate for platinum resistance and raises concern for possible contribution of PARPi in the induction of platinum resistance in recurrent EOC.
Clinical synergy of universal paired tumor genomic and germline sequencing in an unselected, pan-cancer cohort of patients: Greater than the sum of the parts.
Authors: Brandie Heald, Sarah M. Nielsen, Idara Ekpoh, Dana Alexander, Rish Pai, Michael A. Golafshar, Katie Kunze, Pedro Luiz Serrano Uson Junior, Tanios S. Bekaii-Saab, Daniel H. Ahn, Christina Wu, Daniel Esteban Pineda Alvarez, N. Jewel Samadder, Edward D. Esplin
Journal: Journal of Clinical Oncology (2023)

e22537 Background: Germline and tumor next-generation sequencing (NGS) are complementary tests whose benefit in capturing patients (pts) potentially eligible for precision therapies is maximized when the tests are paired, as qualifying pathogenic variants (PVs) are missed if either test was done in isolation (Lincoln et al. 2020). Germline NGS has the additional benefit of informing prevention through surveillance and cascade testing. We highlight the benefits of a universal approach to concurrent testing in a subset of the previously reported cohort of pan-cancer pts who underwent universal germline NGS (Samadder et al. 2020). Methods: Unselected pts with solid tumors underwent an 80+ gene germline panel and 315+ gene tumor panel. Variants in genes unique to the germline or tumor panels, including microsatellite instability (MSI) and tumor mutation burden (TMB), were also evaluated. Results: 104 pts [81.7% White, non-Hispanic, 71.2% male] with 23 cancer types [28% colorectal, 13% lung, 11% prostate, 49% other] were included. Five (5%) pts had no actionable tumor alterations or germline variants identified (Table). 18 pts (17%) had 19 pathogenic germline variants (PGVs) identified, 11 (58%) of which were detected on tumor NGS (Table). 92 pts had &gt;1 tumor alteration identified, of which 12% were confirmed as PGVs (Table). Notably, tumor NGS revealed 81 pts (78%) pts with biomarkers that would could not have been identified with germline testing alone, such as variants in genes not on germline panel (80) or MSI-high (4), or TMB-high (21) status of the tumor. Conclusions: Germline and tumor NGS are complementary tests that often detect different actionable alterations. There is value in confirming both the presence and absence of somatic variants in the germline in order to make appropriate clinical recommendations for the patient and their family members. [Table: see text]
Trends in ovarian cancer incidence and incidence-based mortality: A 15-year population-based analysis.
Authors: Sahana Somasegar, Ravali A. Reddy, Amer Karam
Journal: Journal of Clinical Oncology (2023)

5570 Background: The predicted incidence and incidence-based mortality (IBM) of ovarian cancer (OC) in 2023 is lower than prior years. OC encompasses a range of heterogeneous cancers with subtypes categorized on histology and site of origin. Given differences in survival and treatment paradigms, we aim to characterize trends in OC incidence and IBM based on histology and site of origin to determine what factors are responsible for the decline. Methods: Patients with OC from 2000-2019 were identified from the US Surveillance, Epidemiology, and End Results 17 registry database. Using ICD-O-3 codes, patients with epithelial, stromal, and germ cell cancers of the ovary, fallopian tube, and peritoneum were included. Incidence and IBM were reported as age-adjusted rates and stratified by cancer subtype. Using Joinpoint 4.9.1.0, we characterized piecewise log-linear time trends to identify inflection points in the rates’ annual percentage change (APC). Results: The incidence of epithelial OC decreased significantly from 2004-2019 (APC -1.24%). When stratified by disease stage, this trend was seen in distant disease (APC -2.11%) and unknown/unstaged disease (APC -3.40%); however, there was a significant increase in incidence of local disease (APC +0.83%). There was no significant change in the incidence of germ cell and stromal OC from 2004-2019 in all stages. (APC -0.30% and +0.33%). Among all OC subtypes, there was a significant decline in incidence from 2000-2019 (APC -1.57%) with a sharper decline from 2015-2019 (APC -3.41%). Among all cancer subtypes, the incidence trended down from 2000-2019, with a significant decline from 2015-2019 (APC -2.37%). Similar trends are observed in IBM. Among all stages of epithelial OC, there was a significant decrease in IBM from 2006-2019 (APC -2.02%). When stratified by disease stage, there was a decline in IBM in local disease (APC -7.19%, 2014-2019) and distant disease (APC -2.44%, 2010-2019). There were no changes in IBM of germ cell and stromal OC from 2004-2019 (APC +0.78% and -0.20%). Among all cancers, IBM significantly decreased from 2006-2019 (APC -2.28%). When stratified by disease stage, there was no change among local disease and an increase in regional disease from 2006-2019 with the increase from 2006-2010 (APC +14.35%) compared to 2010-2019 (APC +1.45%). Conversely, there was a significant decrease in IBM for distant disease (APC -2.51% from 2010-2019) and unknown/unstaged disease (APC -3.27% from 2006-2019). Conclusions: There has been an overall decline in incidence and IBM of OC over a 15-year period, primarily driven by the epithelial histology. Over the past 20 years, OC has been increasingly diagnosed at earlier stages with a corresponding improvement in survival. While stage migration and improved survival may contribute to these trends, they do not entirely explain them. As new treatments become available, the incidence and IBM of OC may further decline.
Malignancy in patients with sickle cell disease: A single center experience.
Authors: Shivani Sharma, Nakoma Walker, Shidestini Chanta Martinez, Poornima Ramadas, Runhua Shi, Samip R. Master, Richard P. Mansour
Journal: Journal of Clinical Oncology (2023)

e22551 Background: The development of malignancy in patients with sickle cell disease has been documented in multiple case reports and case series. The incidence of malignancy in patients with sickle cell disease is unknown. Large national databases like the National Cancer Database, North American Association of Central Cancer Registries, and SEER do not collect data on the presence of sickle cell disease. This has made it difficult to calculate the incidence of malignancy in this patient population. In our study, we aim to calculate the prevalence of malignancy in sickle cell patients following our institution. Methods: After IRB approval, a retrospective analysis was conducted of adult sickle cell disease patients being followed at our Hematology outpatient clinic. We included patients aged &gt; / = 18 years with sickle cell disease (HBSS, HBSC, HBS-beta thalassemia) as per hemoglobin electrophoresis, who were followed at the clinic from 1/1/2017 to 10/1/2022. We excluded prisoners. We did an extensive chart review to identify patients with a diagnosis of malignancy by pathology. Variables of age, sex, race, type of sickle cell disease, type of malignancy, age at the diagnosis of malignancy, and treatment were collected. Continuous descriptive data were summarized as means. Categorical data were summarized with a sample percentage. The prevalence of malignancy was calculated. SAS for windows 9.4 was used for analysis. Results: 438 patients with sickle cell disease were identified from 2017 to 2022. All the patients were African American. Their ages ranged from 16 to 84 with a mean of 35 years. Of these patients 53 % were females and 47 % were male. 62% had HBSS disease, 25 % had HBSC and 13% had HBS beta thalassemia genotype. 4 patients were diagnosed with malignancy. All 4 patients were female. The prevalence of malignancy was calculated as 0.91%. Conclusions: We found four patients with malignancy in the patient population with sickle cell disease at our hematology clinic. This data is based on limited sample size. The incidence of malignancy in sickle cell patients should be calculated in a larger population base. Further studies can be done to determine if a single type of sickle cell genotype increases the risk of malignancy. All the centers where sickle cell patients are followed should monitor the patients prospectively for the development of malignancy.[Table: see text]
Genomic mechanisms of RET inhibitor sensitivity and resistance in RET-fusion positive cancer cells.
Authors: John Heymach, Monique B. Nilsson, Xiaofang Huo, Ashwani Kumar, Jun He, Ralf Kittler
Journal: Journal of Clinical Oncology (2023)

e21029 Background: RET fusions occur in 2-3% of lung cancer cases, and there are currently two FDA-approved RET-specific inhibitors (RETi), selpercatinib and pralsetinib. RET fusions are heterogeneous and the impact of specific fusion partners and their unique breakpoints on drug sensitivity is poorly understood. Moreover, while patients may be initially sensitive to RETi treatment, therapeutic resistance eventually emerges, and studies have shown that RET-dependent mechanisms of resistance include acquired resistance mutations that alter drug binding. We sought to investigate mechanisms of sensitivity and resistance to RET inhibitors in RET-fusion positive lung cancer in effort to improve treatment options and clinical outcomes in this patient population. Methods: We characterized the landscape of RET-fusions and -mutations in non-small cell lung cancer (NSCLC). KIF5B-RET, CCDC6-RET, and NCOA4-RET were the most frequently observed RET fusions in NSCLC. To investigate the drug sensitivity profile of individual RET fusion variants, we generated a panel of Ba/F3 cells expressing various RET fusion variants and evaluated in vitro sensitivity to RETi including selpercatinib, pralsetinib, vandetinib, cabozantinib, TPX-0046, lovatinib, and ponatinib. We observed that unique RET fusions impart differential sensitivities to RET inhibitors. For example, cells expressing KIF-RET (K15, R12) were highly sensitive to selpercatinib, pralsetinib, and ponatinib, whereas cells expressing KIF-RET (K22, R12) were likewise sensitive to selpercatinib and pralsetinib but were less sensitive to ponatinib. We next established a cell line (MDA-L-30) from a patient harboring a RET-fusion (KIF-RET; K15, R12) and observed a RETi sensitivity profile similar to that observed using the BaF3 system. Results: Next, we employed the LentiMutate approach to rapidly identify genomic mechanisms of RETi resistance. In cells expressing the KIF5B-RET (K15, R12) fusion, the G810S mutation was associated with acquired resistance to both selpercatinib and pralsetinib, consistent with prior reports and clinical observations. However, V804M/E and M918T mutations were associated with acquired resistance to selpercatinib but not pralsetinib, and L730I/V and E732K mutations were associated with resistance to pralsetinib but not selpercatinib. Conclusions: Taken together, these data indicate that individual RET fusion variants with diverse fusion partner breakpoints have distinct drug sensitivity profiles and that secondary resistance mutations may be non-overlapping between RETi. These findings support the need to comprehensively characterize RET-dependent mechanisms of resistance in order to provide therapeutic recommendations for treating RET-fusion driven cancers.
Real-world experience of tebentafusp for uveal melanoma via an Australian access program.
Authors: Andrisha Jade Inderjeeth, Josh Hurwitz, Anthony M. Joshua, Damien Kee
Journal: Journal of Clinical Oncology (2023)

e21554 Background: Uveal melanoma (UM) is a rare melanoma subset, with distinct biology, genetics, and limited active therapies. Tebentafusp (tebe) has demonstrated a survival advantage however low response rates and a toxicity profile making real-world administration challenging. Methods: Data was retrospectively collected for patients (pt) enrolled into a tebentafusp access program at two tertiary Australian centres. Data fields included: baseline patient, disease and prior treatment characteristics; and tebe administration, response, toxicity and survival outcomes. Results: From May 2021 to February 2023, 19 pt received tebe for UM: 7 males, average age 61 years (range 39-86). All pt presented with local disease at diagnosis, with time to metastases greater than 12 months (mo) in 15/19. Prior to tebe, all patients had hepatic and 6/19 extra-hepatic metastases (6 bone, 4 lymph node, 2 peritoneal, 2 dermal and/or subcutaneous). Baseline PET scan demonstrated FDG-avid disease in 13/14. Primary disease treatment included enucleation (7/19) and radiotherapy 13/19). For advanced disease, prior systemic therapies included: none (12/19); anti-PD1 (3) or anti-CTLA4 (2) as monotherapy; or in combination (5); and anti-PD1 with anti-LAG3 (2). Prior to tebe baseline LDH was elevated in 10/19 (53%) and average neutrophil to lymphocyte ratio was 9.22 (range 0.9-49.5). The median time receiving tebe was 5.5 mo (range &lt; 1-18). The median progression free survival (PFS) was &lt; 3mo. 5 pt remain on tebe with 2 pt treated with tebe beyond 12 and 18mo duration. Best response obtained by PET or cross-sectional imaging was: a partial response in 4/19, stable/mixed in 4/19, progressive disease in 8/19, and unknown/not evaluable in 3/19. The majority of patients ceased tebe due to disease progression (10), change of therapy (4) or death (2). Only one patient ceased due to toxicity. At last review 14/19 (74%) patients were still alive and 4/19 had received one or more lines of systemic therapy after tebe including immunotherapy (1), targeted therapy (1) and/or clinical trials (4). Common adverse events included: rash (63%), hypotension (47%), pruritis (42%) and pyrexia (32%). Supportive measures were required (e.g. hydration, antihistamines, topical steroids) for 13 patients. Cytokine release syndrome (CRS) was reported in 63% (12/19) with only 3 demonstrating grade 2 severity. CRS management included oral (1) or intravenous steroids (2) and zero patients required additional immunosuppression. The median number of cycles administered as an inpatient was 3 (range 2-10). Conclusions: Within experienced tertiary centres tebe could be safely administered outside of a clinical trial setting. Median time on treatment greatly exceeds progression free survival, likely due to unique response characteristics and limited access to subsequent therapy. Identifying features that enrich for clinical benefit remain necessary for optimising tebe use.